Dr. Makhani is a pediatric neurologist whose long-term goal is to implement strategies to prevent multiple sclerosis in children at risk. The training and mentored research experience proposed will enable her to develop expertise in conducting longitudinal cohort studies and in using MRI as a clinical and research tool. Dr. Makhani has assembled an expert and committed team of mentors and advisors to help her. Dr. Eugene Shapiro, her primary mentor, is a recognized leader in clinical epidemiological research and Dr. Daniel Pelletier (co-mentor) is a world expert in using MRI to study the biology of multiple sclerosis. Dr. Makhani will take courses at Yale on the theory and application of use of imaging techniques in neurological research and will spend six months with Dr. Pelletier getting hands-on training in his Advanced Imaging in Multiple Sclerosis lab at the University of Southern California. She will also take advanced courses at Yale in genetics, as well as in the analysis of imaging data, of longitudinal data, of time-to-event data and of clinical trials. Children with multiple sclerosis, the most common autoimmune disease of the central nervous system, have high relapse rates and may develop disability at a young age, but treatment may improve both. The typical MRI findings of multiple sclerosis have been found in people without any symptoms of multiple sclerosis who underwent MRI scans of the brain for other reasons (e.g., head trauma). This clinical scenario has been termed the radiologically isolated syndrome (RIS). Among adults with RIS, 34% developed clinical neurological symptoms consistent with multiple sclerosis within five years of the initial abnormal MRI. In adults with RIS, age <37 years, male sex and spinal cord lesions on MRI were associated with developing clinical neurological symptoms. We do not know either the risk of or what factors are associated with developing a clinical diagnosis of multiple sclerosis in children with RIS. We will conduct a mixed historical and prospective longitudinal cohort study to determine both the likelihood of and the factors (clinical, demographic, MRI, laboratory and genetic) associated with the development of a clinical diagnosis of multiple sclerosis in children with RIS. This study will help determine which children with RIS are at greatest risk of a clinical multiple sclerosis and will set the stage for intervention trials to prevent or to delay onset of clinical multiple sclerosis in these children. Upon completion of this award, Dr. Makhani will be the only pediatric neurologist in the world with formal fellowship training in pediatric multiple sclerosis and formal training in using neuroimaging techniques for research in pediatric multiple sclerosis. She will have conducted the first and only longitudinal cohort study of children with RIS in collaboration with her Pediatric RIS Consortium, that will provide the necessary infrastructure for future studies, and she will be well poised to apply for funding to become an independent clinician-scientist.